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首页> 外文期刊>Journal of Neurochemistry: Offical Journal of the International Society for Neurochemistry >Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis
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Protein misfolding cyclic amplification induces the conversion of recombinant prion protein to PrP oligomers causing neuronal apoptosis

机译：蛋白错折叠循环扩增诱导重组病毒蛋白转化为PrP寡聚体，导致神经元凋亡

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摘要

The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into -state oligomers. Herein, we demonstrate that -state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full-length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP-induced neurotoxicity. We have characterized protein misfolding cyclic amplification-induced monomer-to-oligomer conversion of PrP from three species using western blotting, circular dichroism, size-exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting -oligomers are toxic to primary mouse cortical neurons independent of the presence of PrPC in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer-induced apoptosis via regulation of Bcl-2, Bax, and caspase-3 in both wild-type and PrP-/- cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain.
机译：神经毒性病毒蛋白（PrP）寡聚物的形成被认为是the病毒疾病发展的关键步骤。最近，已经确定重组PrP的超声处理和振动可以将PrP单体转化为状态低聚物。在本文中，我们证明了可通过重组全长仓鼠，人，兔和突变的兔PrP的蛋白质错误折叠循环扩增来生成-state寡聚PrP，并且这些寡聚物可用于后续研究PrP诱导的机制神经毒性。我们使用蛋白质印迹，圆二色性，尺寸排阻色谱法和对蛋白酶K（PK）消化的抵抗力，从三个物种中表征了蛋白质错折叠循环扩增诱导的PrP的单体向低聚物的转化。我们进一步表明，所有所得的寡聚体均对原代小鼠皮层神经元有毒，而与神经元中PrPC的存在无关，而相应的单体PrP无毒。此外，我们发现这种毒性是寡聚体通过调节野生型和PrP-/-皮质神经元中的Bcl-2，Bax和caspase-3诱导的凋亡的结果。我们希望这些结果有助于我们对大脑中病毒转化的理解。

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